The limited availability of the potent antitumour compound paclitaxel (1), isolated from the bark of the Pacific yew tree (Taxus Brevifolia), has motivated scientists to develop an alternative paclitaxel source (Farina (ed.), The Chemistry and pharmacology of Taxol.RTM. and its derivatives, Elsevier Science Amsterdam, 1995, p 7-53). An attractive alternative is the semisynthesis from a paclitaxel precursor isolated from a renewable source. Though many precursors have been isolated and converted into paclitaxel and analogues, these semisyntheses are either too complex, (for example taxine B (Wiegerinck et al., J. Org. Chem., 1996, 61, 7092)), or the amount of isolated precursor is too low (like baccatin III (2) (Halsall et al., J. Chem. Soc., Chem. Commun., 1970, 216)) to be economically feasible. A useful precursor was discovered by Potier et al (C. R. Acad. Sc., 1981, 293, serie II, 501), who isolated 10-deacetylbaccatin III (3) from the leaves of the European yew (Taxus Baccata). Meanwhile it has been demonstrated that this precursor can be isolated relatively easy and in significant amounts (Pilard et al., PCT Application, WO 94/07882). ##STR1##
In the first reported semisynthesis by Greene et al (J. Am. Chem. Soc., 1988, 110, 5917), 10-deacetylbaccatin III is converted into paclitaxel in four steps (scheme 1). Under what are claimed to be carefully optmised conditions, 10-deacetylbaccatin III (3) is protected at the C7-position using 20 equivalents of triethylsilyl chloride in pyridin at 0.degree. C. (c.y. 78%). Acylation with 10 equivalents of acetylchloride for 48 hours at 0.degree. C. results in 7-triethylsilyl-baccatin III in 86% yield. Treatment with excess protected side chain in the presence of di-2-pyridyl carbonate (DPC) and 4 thylamino pyridine (DMAP) at 73.degree. C. for 100 hours gave protected paclitaxel in 80% yield at 50% conversion. Deprotection of the C7- and C2'-position in 89% yield gave paclitaxel (1) in an overall yield of 24% starting from 10-deacetylbaccatin III (3) (48% when based on 50% conversion in step three). ##STR2##
The attachment of the side chain, the weakest point in the synthesis described above, has been improved through the years. For example, Holton et al. developed a process involving the use of .beta.-lactam (4) to couple to 7-triethylsilylbaccatin III in 92% yield to obtain paclitaxel in an overall yield of 61% from 10-deacetylbaccatin III (Holton et al., Eur. Patent Application, 0,400,971). A second improved introduction of the side chain in 100% yield at 77% conversion involves an oxazinone (5). The overall yield from 10-deacetylbaccatin III is 66% (Holton et al., Eur. Patent Application 0,428,376). A third example of a high-yield side chain attachment to 7-triethylsilylbaccatin III uses oxazolidine (6) (94% yield), resulting in an overall yield of 64% (Greene et al., J. Chem. Soc., Chem. Commun., 1994, 2591). ##STR3##
The examples above illustrate that the weak point in the paclitaxel semisynthesis is no longer the attachment of the protected side chain but the conversion of 10-deacetylbaccatin III into C7-O-protected baccatin III.